Inhibiting triglyceride synthesis improves hepatic steatosis but exacerbates liver damage and fibrosis in obese mice with nonalcoholic steatohepatitis
Inhibiting triglyceride synthesis improves hepatic steatosis but exacerbates liver damage and fibrosis in obese mice with nonalcoholic steatohepatitis
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DOI：
10.1002/hep.21655
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发表时间：
2007-06-01
期刊：
影响因子：
13.5
通讯作者：
Diehl, Anna Mae
中科院分区：
文献类型：
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作者：
Yamaguchi, Kanji;Yang, Liu;Diehl, Anna Mae
在非酒精性脂肪性肝病（NAFLD）的早期阶段，甘油三酯在肝细胞中积累。二酰基甘油酰基转移酶2（DGAT 2）催化肝细胞甘油三酯生物合成的最后一步。DGAT 2反义寡核苷酸（阿索）治疗显着改善肝脏脂肪变性在以前的研究肥胖小鼠。根据NAFLD进展的2次打击假设，肝脂肪变性是非酒精性脂肪性肝炎（NASH）和纤维化的危险因素。为了评估这一假设，我们在蛋氨酸和胆碱（MCD）缺乏饮食诱导的NASH小鼠模型中抑制DGAT 2。对6周龄遗传性肥胖和糖尿病mate db/db小鼠饲喂对照或MCD饲料4周或8周。MCD饮食组每周两次腹腔内给予25 mg/kg DGAT 2阿索或生理盐水。评价了肝脂肪变性、损伤、纤维化、脂质过氧化/氧化应激标志物和全身胰岛素敏感性。与对照组相比，喂食盐水处理的MCD饲料的小鼠的肝脏脂肪变性、坏死性炎症和纤维化增加。用DGAT 2阿索处理喂食MCD饲料的小鼠4周和8周可减少肝脏脂肪变性，但增加肝脏游离脂肪酸、细胞色素P4502 E1、脂质过氧化/氧化应激标志物、小叶坏死性炎症和纤维化。尽管肿瘤坏死因子α的肝脏表达降低，血清脂联素升高，全身胰岛素敏感性显著改善，但仍发生肝损伤进展。结论：该小鼠模型的结果表明，甘油三酯的积累可能是预防NAFLD进行性肝损伤的保护机制。
In the early stages of nonalcoholic fatty liver disease (NAFLD), triglycerides accumulate in hepatocytes. Diacylglycerol acyltransferase 2 (DGAT2) catalyzes the final step in hepatocyte triglyceride biosynthesis. DGAT2 antisense oligonucleotide (ASO) treatment improved hepatic steatosis dramatically in a previous study of obese mice. According to the 2-hit hypothesis for progression of NAFLD, hepatic steatosis is a risk factor for nonalcoholic steatohepatitis (NASH) and fibrosis. To evaluate this hypothesis, we inhibited DGAT2 in a mouse model of NASH induced by a diet deficient in methionine and choline (MCD). Six-week-old genetically obese and diabetic mate db/db mice were fed either the control or the MCD diet for 4 or 8 weeks. The MCD diet group was treated with either 25 mg/kg DGAT2 ASO or saline intraperitoneally twice weekly. Hepatic steatosis, injury, fibrosis, markers of lipid peroxidation/oxidant stress, and systemic insulin sensitivity were evaluated. Hepatic steatosis, necroinflammation, and fibrosis were increased in saline-treated MCD diet-fed mice compared to controls. Treating MCD diet-fed mice with DGAT2 ASO for 4 and 8 weeks decreased hepatic steatosis, but increased hepatic free fatty acids, cytochrome P4502E1, markers of lipid peroxidation/oxidant stress, lobular necroinflammation, and fibrosis. Progression of liver damage occurred despite reduced hepatic expression of tumor necrosis factor alpha, increased serum adiponectin, and striking improvement in systemic insulin sensitivity. Conclusion: Results from this mouse model would suggest accumulation of triglycerides may be a protective mechanism to prevent progressive liver damage in NAFLD.